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(American Journal of Pathology. 2003;163:1735-1741.)
© 2003 American Society for Investigative Pathology

Short Communication

Susceptibility to Anthrax Lethal Toxin Is Controlled by Three Linked Quantitative Trait Loci

Ryan D. McAllister^*, Yogendra Singh, Wendy D. du Bois, Michael Potter, Thomas Boehm, Nathan D. Meeker^¶, Parley D. Fillmore^||, Lisa M. Anderson^**, Matthew E. Poynter^** and Cory Teuscher^**

From Department of Microbiology,^* University of Illinois, Urbana, Illinois; the Institute of Genomics and Integrative Biology, Delhi, India; National Cancer Institute, National Institutes of Health, Bethesda, Maryland; Department of Developmental Immunology, Max Planck Institute of Immunobiology, Freiburg, Germany; Department of Pediatrics,^¶ Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Veterinary Pathobiology,^|| University of Illinois at Urbana-Champaign, Urbana, Illinois; and Department of Medicine,^** University of Vermont, Burlington, Vermont

Anthrax lethal toxin (LT) is the principal virulence factor associated with lethal pathologies following infection with Bacillus anthracis. Macrophages are the primary effector cells mediating lethality since macrophage-depleted mice are resistant to LT challenge. Recently, Ltxs1, the gene controlling differential susceptibility of murine macrophages to cytolysis following in vitro exposure to LT, was identified as Kif1c. To directly assess the in vivo role of Kif1c alleles in mortality, we studied a panel of interval-specific recombinant congenic lines carrying various segments of central chromosome 11 derived from LT-resistant DBA/2 mice on the LT-susceptible BALB/c background. The results of this study reveal that mortality is controlled by three linked quantitative trait loci (QTL): Ltxs1/Kif1c (42–43 cM), Ltxs2 (35–37 cM), and Ltxs3 (45–47 cM). The Ltxs3 interval encompasses Nos2, which is an attractive candidate gene for Ltxs3. In this regard, we demonstrate that selective, pharmacologically based inhibition of Nos2 activity in vivo partially overrides genetic resistance to LT and that Nos2 expression as determined by reverse transcription-polymerase chain reaction differs significantly between DBA/2 and BALB/c macrophages. Additionally, to recapitulate dominant resistance to mortality as seen in (BALB/c x DBA/2) F₁ hybrids, DBA/2 alleles are required at all three QTL.

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